THE PROGRESSIVE DIFFERENTIATION OF PRIMED T-CELLS IS ASSOCIATED WITH AN INCREASING SUSCEPTIBILITY TO APOPTOSIS
THE PROGRESSIVE DIFFERENTIATION OF PRIMED T-CELLS IS ASSOCIATED WITH AN INCREASING SUSCEPTIBILITY TO APOPTOSIS
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DOI：
10.1002/eji.1830240417
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发表时间：
1994-04-01
影响因子：
5.4
通讯作者：
AKBAR, AN
中科院分区：
文献类型：
--
作者：
SALMON, M;PILLING, D;AKBAR, AN
最近的研究表明，T细胞对召回抗原的记忆存在于有丝分裂间期较短的T细胞克隆中。在人类中，这样的细胞表达一种称为CD45RO的白细胞共同抗原的同种形式。然而，这些被激活的T细胞在初始激活后的命运鲜为人知，因为没有可用的标记来区分最近被激活的细胞和长期建立的克隆细胞。这份报告集中在一种预置的CD4(+)T细胞的光谱上，其特征是两个CD45表位：CD45RB和CD45RO的表达呈反向关系。我们发现，启动的CD4(+)T细胞经历了许多周期的分裂，从CD45RB(明亮)O(迟钝)状态到CD45RB(迟钝)O(明亮)状态，导致T细胞受体可变区使用在这一特定人群中的高度扭曲分布。由CD45RB(明亮)向CD45RB(暗淡)的转变所定义的渐进性分化与bcl2的逐渐丧失和Fas的表达增加是平行的，这两个特征与细胞凋亡倾向增加有关。与此同时，高度分化的CD45RB(Dull)细胞选择性地失去合成IL-2的能力，IL-2是一种在防止T细胞凋亡方面特别有效的细胞因子，尽管它们会产生高水平的IL-4。在缺乏外源性IL-2的刺激下，无法产生足够水平的IL-2会导致启动的CD45RB(Dull)细胞发生凋亡。这些观察结果表明，高度分化的T细胞对外源性IL-2的可获得性具有至关重要的依赖性，这表明T细胞记忆的持久性受到持续循环启动细胞的主要限制，也是维持体内T细胞内稳态的重要机制。
Recent studies have suggested that T cell memory for recall antigens resides in clones of primed T cells with a short inter-mitotic half-life. In humans such cells express an isoform of the leukocyte common antigen termed CD45RO. Nevertheless, little is known of the fate of these primed T cells after initial activation, since no markers are available to distinguish recently primed cells from long-established clones. This report is focused on a spectrum of primed CD4(+) T cells characterized by an inverse relationship between the expression of two CD45 epitopes: CD45RB and CD45RO. We show that primed CD4(+) T cells progress through many cycles of division from a CD45RB(bright)O(dull) to a CD45RB(dull)O(bright) state, resulting in a highly skewed distribution of the T cell receptor variable region usage within this particular population. The progressive differentiation defined by the shift from CD45RB(bright) to CD45RB(dull) is paralleled by the gradual loss of bcl-2 and gain of Fas expression, two features associated with an increased propensity for apoptosis. At the same time, the highly differentiated CD45RB(dull) cells selectively lose the capacity to synthesize interleukin (IL)-2, a cytokine which is particularly effective in preventing T cell apoptosis, although they produce high levels of IL-4. The inability to produce adequate levels of IL-2 leads to the apoptosis of primed CD45RB(dull) cells, when they are stimulated in the absence of exogenous IL-2. These observations show the crucial dependence of highly differentiated T cells on the availability of exogenous IL-2, and suggest both a major constraint for the persistence of T cell memory maintained by continually cycling primed cells, and an important mechanism contributing to the maintenance of T cell homeostasis in vivo.